2-(2-fluorophenyl)acetyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 46.0 g of (R)-4-phenyl-2-oxazolidinone in 300 g (338 mL) of peroxide-free tetrahydrofuran is cooled to −5 to 0° C. (bath temperature −10 to −5° C.) over a period of 15 minutes. 145.2 g (166.8 mL) of 25% w/w potassium t-amylate/toluene solution is added over a period of 25 minutes while maintaining an internal temperature below 0° C. The reaction mixture is warmed to 20±5° C. within 1 hour and stirred at this temperature for 2.5-3 hours. The mixture is cooled to −15 to −5° C. over a period of 30 minutes, and crude 2-fluorobenzenacetyl chloride (obtained above) is added over a period of 45 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.). After the addition is completed, the mixture is warmed to 20±5° C. over a period of 1 hour, and diluted with 100 mL of toluene. This is added to 500 mL of saturated citric acid monosodium salt solution (100 g in 450 g of water) and the mixture is stirred for 5 minutes. The organic layer is separated, and washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each. The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 450 mL of t-butyl methyl ether and the mixture is heated to reflux (53-58° C.) to obtain a solution; 225 mL of t-butyl methyl ether is then distilled off at atmospheric pressure (bath temperature 60-65° C.). The resulting mixture is cooled to 20-25° C., and stirred at this temperature for 16 hours, then cooled to −5 to 0° C. and stirred at this temperature for additional 2 hours and filtered. The resulting solid is dried under vacuum (66-76 mm Hg) at 45-50° C. for 12 hours to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a white crystalline solid. while maintaining an internal temperature below 0° C The mixture is cooled to −15 to −5° C. over a period of 30 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.) After the addition the mixture is warmed to 20±5° C. over a period of 1 hour the mixture is stirred for 5 minutes The organic layer is separated washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 46.0 g of (R)-4-phenyl-2-oxazolidinone in 300 g (338 mL) of peroxide-free tetrahydrofuran is cooled to −5 to 0° C. (bath temperature −10 to −5° C.) over a period of 15 minutes. 145.2 g (166.8 mL) of 25% w/w potassium t-amylate/toluene solution is added over a period of 25 minutes while maintaining an internal temperature below 0° C. The reaction mixture is warmed to 20±5° C. within 1 hour and stirred at this temperature for 2.5-3 hours. The mixture is cooled to −15 to −5° C. over a period of 30 minutes, and crude 2-fluorobenzenacetyl chloride (obtained above) is added over a period of 45 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.). After the addition is completed, the mixture is warmed to 20±5° C. over a period of 1 hour, and diluted with 100 mL of toluene. This is added to 500 mL of saturated citric acid monosodium salt solution (100 g in 450 g of water) and the mixture is stirred for 5 minutes. The organic layer is separated, and washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each. The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 450 mL of t-butyl methyl ether and the mixture is heated to reflux (53-58° C.) to obtain a solution; 225 mL of t-butyl methyl ether is then distilled off at atmospheric pressure (bath temperature 60-65° C.). The resulting mixture is cooled to 20-25° C., and stirred at this temperature for 16 hours, then cooled to −5 to 0° C. and stirred at this temperature for additional 2 hours and filtered. The resulting solid is dried under vacuum (66-76 mm Hg) at 45-50° C. for 12 hours to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a white crystalline solid. while maintaining an internal temperature below 0° C The mixture is cooled to −15 to −5° C. over a period of 30 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.) After the addition the mixture is warmed to 20±5° C. over a period of 1 hour the mixture is stirred for 5 minutes The organic layer is separated washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.)

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 50.0 g of o-fluorophenylacetic acid in 150 mL of toluene and 2.2 g of N,N-dimethylformamide is added to 50.2 g (31.7 mL) of thionyl chloride with efficient stirring over a period of 20 minutes while maintaining an internal temperature of 20-25° C. After addition, the mixture is stirred for 3 hours at 20-25° C., and concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 2-fluorobenzenacetyl chloride as an oil. After addition the mixture is stirred for 3 hours at 20-25° C. concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 4(R)-phenyl-2-oxazolidinone (340 g, 2.08 mol) in THF (8000 mL), is added n-BuLi (2.5 M, 920 mL, 1.1 eq). The reaction mixture is stirred for 20 minutes and 2-fluorobenzeneacetyl chloride (358 g, 2.08 mol) is added. After 2 hours the reaction mixture is quenched with saturated NH4Cl solution (1×1000 mL). The organic layer is separated, washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL) and then concentrated in vacuo. This procedure yields 3-[(2-fluorophenyl)-acetyl]-4(R)-phenyl-2-oxazolidinone. After 2 hours the reaction mixture is quenched with saturated NH4Cl solution (1×1000 mL) The organic layer is separated washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluorophenylacetic acid (450 g, 3.0 mol) in CH2Cl2 (900 mL) is added SOCl2 (714 g, 6 mol) dropwise. After addition is complete, the reaction mixture is heated to reflux for 2 hours. Subsequently, the solvent is removed in vacuo after which vacuum distillation of the resulting oil provides 2-fluorobenzeneacetyl chloride. After addition the reaction mixture is heated to reflux for 2 hours Subsequently, the solvent is removed in vacuo after which vacuum distillation of the resulting oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluorophenylacetic acid (450 g, 3.0 mol) in CH2Cl2 (900 mL) is added SOCl2 (714 g, 6 mol) dropwise. After addition is complete, the reaction mixture is heated to reflux for 2 hours. Subsequently, the solvent is removed in vacuo after which vacuum distillation of the resulting oil provides 2-fluorobenzeneacetyl chloride. After addition the reaction mixture is heated to reflux for 2 hours Subsequently, the solvent is removed in vacuo after which vacuum distillation of the resulting oil

Conditions: temp:0.00; pressure:0.00; stir: